Oncotarget 7469 www.impactjournals.com/oncotarget www.impactjournals.com/oncotarget/ Oncotarget, Vol. 7, No. 7 Selective brain penetrable Nurr1 transactivator for treating Parkinson’s disease Jun Wang 1,2 , Weina Bi 1 , Wei Zhao 1 , Merina Varghese 1 , Rick J. Koch 3 , Ruth H. Walker 3 , Roshantha A. Chandraratna 4 , Martin E. Sanders 4 , Amanda Janesick 5 , Bruce Blumberg 5 , Libby Ward 1 , Lap Ho 1 and Giulio M. Pasinetti 1,2 1 Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA 2 Geriatric Research, Education and Clinical Center, Bronx, NY, USA 3 Department of Neurology, James J. Peters Veterans Affairs Medical Center, Bronx, NY, USA 4 Io Therapeutics Inc., Santa Ana, CA, USA 5 Departments of Developmental and Cell Biology, and Pharmaceutical Sciences, University of California, Irvine, CA, USA Correspondence to: Giulio M. Pasinetti, email: giulio.pasinetti@mssm.edu Keywords: brain bioavailable, dopaminergic, nuclear receptor related-1 protein, Parkinson’s disease, retinoid X receptor, Gero- target Received: September 23, 2015 Accepted: January 23, 2016 Published: February 04, 2016 ABSTRACT Parkinson’s disease (PD) is one of the most common movement disorders, and currently there is no effective treatment that can slow disease progression. Preserving and enhancing DA neuron survival is increasingly regarded as the most promising therapeutic strategy for treating PD. IRX4204 is a second generation retinoid X receptor (RXR) agonist that has no cross reactivity with retinoic acid receptors, farnesoid X receptor, liver X receptors or peroxisome proliferator-activated receptor PPARγ. We found that IRX4204 promotes the survival and maintenance of nigral dopaminergic (DA) neurons in a dose-dependent manner in primary mesencephalic cultures. Brain bioavailability studies demonstrate that IRX4204 can cross the blood brain barrier and reach the brain at nM concentration. Oral administration of IRX4204 can activate nuclear receptor Nurr1 downstream signaling in the substantia nigra (SN) and attenuate neurochemical and motor defcits in a rat model of PD. Our study suggests that IRX4204 represents a novel, potent and selective pharmacological means to activate cellular RXR-Nurr1 signaling and promote SN DA neuron survival in PD prevention and/or treatment. INTRODUCTION Parkinson’s disease (PD) is the second most common neurodegenerative disease of aging, which currently affects approximately 1-2% of the world’s population over age 65. The number of individuals with PD is expected to double by 2030, affecting up to 9.3 million [1]. PD is associated with increased disability, lower quality of life, increased mortality, and increased healthcare costs across all stages of the disease. The annual economic impact of PD in the United States alone is estimated at $10.8 billion [2]. The molecular mechanisms underlying the disease are unknown, but are likely to involve interactions among genetic and environmental factors. The protein α-synuclein is a central component in PD pathogenesis [3, 4]; α-synuclein aggregation with Lewy body formation in substantia nigra DA neurons is a main pathological feature leading to DA neuron cell death [5]. The motor symptoms of PD are believed to begin after 40-60% of the dopamine cells in the substantia nigra (SN) pars compacta are lost [6]. Progression of motor symptoms is related to dopamine cell loss and can be assessed clinically using the Unifed Parkinson’s Disease Rating Scale part III (UPDRS-3), which is sensitive to treatment related changes. Motor symptoms produce signifcant disability, worsen quality of life, and advance even when treated optimally with currently available symptomatic therapies. Current therapies for PD are symptomatic treatments for motor complications of the disease; to date there are no disease modifying drug treatments conclusively shown to be neuroprotective or that slow disease progression [7].